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Epigenetic modification of PKMζ rescues aging-related cognitive impairment.

ABSTRACT: Cognition is impacted by aging. However, the mechanisms that underlie aging-associated cognitive impairment are unclear. Here we showed that cognitive decline in aged rats was associated with changes in DNA methylation of protein kinase Mζ (PKMζ) in the prelimbic cortex (PrL). PKMζ is a crucial molecule involved in the maintenance of long-term memory. Using different behavioral models, we confirmed that aged rats exhibited cognitive impairment in memory retention test 24 h after training, and overexpression of PKMζ in the PrL rescued cognitive impairment in aged rats. After fear conditioning, the protein levels of PKMζ and the membrane expression of GluR2 increased in the PrL in young and adult rats but not in aged rats, and the levels of methylated PKMζ DNA in the PrL decreased in all age groups, whereas the levels of unmethylated PKMζ DNA increased only in young and adult rats. We also found that environmentally enriched housing reversed the hypermethylation of PKMζ and restored cognitive performance in aged rats. Inactivation of PKMζ prevented the potentiating effects of environmental enrichment on memory retention in aged rats. These results indicated that PKMζ might be a potential target for the treatment of aging-related cognitive impairment, suggesting a potential therapeutic avenue.

SUBMITTER: Chen C

PROVIDER: S-EPMC4772003 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Project description:Measures of cerebrovascular reactivity (CVR) are used to judge the health of the brain vasculature. In this study, we report the use of several different analyses of blood oxygen dependent (BOLD) fMRI responses to CO2 to provide a number of metrics of CVR based on the sigmoidal resistance response to CO2. To assess possible differences in these metrics with age, we compiled atlases reflecting voxel-wise means and standard deviations for four different age ranges and for a group of patients with mild cognitive impairment (MCI) and compared them. Sixty-seven subjects were recruited for this study and scanned at 3T field strength. Of those, 51 healthy control volunteers between the ages of 18-83 were recruited, and 16 (MCI) subjects between the ages of 61-83 were recruited. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm while monitoring end-tidal partial pressures of CO2. Surprisingly, some resistance sigmoid parameters in the oldest control group were increased compared to the youngest control group. Resistance amplitude maps showed increases in clusters within the temporal cortex, thalamus, corpus callosum and brainstem, and resistance reserve maps showed increases in clusters within the cingulate cortex, frontal gyrus, and corpus callosum. These findings suggest that some aspects of vascular reactivity in parts of the brain are initially maintained with age but then may increase in later years. We found significant reductions in all resistance sigmoid parameters (amplitude, reserve, sensitivity, midpoint, and range) when comparing MCI patients to controls. Additionally, in controls and in MCI patients, amplitude, range, reserve, and sensitivity in white matter (WM) was significantly reduced compared to gray matter (GM). WM midpoints were significantly above those of GM. Our general conclusion is that vascular regulation in terms of cerebral blood flow (CBF) responsiveness to CO2 is not significantly affected by age, but is reduced in MCI. These changes in cerebrovascular regulation demonstrate the value of resistance metrics for mapping areas of dysregulated blood flow in individuals with MCI. They may also be of value in the investigation of patients with vascular risk factors at risk for developing vascular dementia.

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Epigenetic modification of PKMζ rescues aging-related cognitive impairment.

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